An amphiphilic block copolymer includes a hydrophilic polymer block and a hydrophobic polymer block. Since the hydrophilic polymer block is in direct contact with blood proteins and cell membranes in vivo, a biocompatible polymer such as polyethylene glycol or monomethoxypolyethylene glycol has been used as the hydrophilic polymer block. Meanwhile, the hydrophobic polymer block improves affinity to hydrophobic drugs, and particular examples thereof that have been used to date include biodegradable polymers such as polylactide, polyglycolide, poly(lactic-co-glycolide), polycaprolactone, polyaminoacids or polyorthoesters. Particularly, polylactide derivatives have been applied to drug carriers in various forms, because they have excellent biocompatibility and are hydrolyzed into non-harmful lactic acid in vivo. Polylactide derivatives have various physical properties depending on their molecular weights. In addition, polylactide derivatives have been developed as various forms including microspheres, nanoparticles, polymeric gels and implant agents.
When an amphiphilic block copolymer is used as a drug carrier, drug release rates are controlled by modifying the composition of the hydrophilic polymer block and the hydrophobic polymer block, the molecular weight of each block, etc. In controlling drug release rates precisely, purity of the amphiphilic block copolymer is important. Monomers are used to prepare the hydrophobic biodegradable polymer block. However, unreacted monomers contained in the final amphiphilic block copolymer may result in a broad molecular weight distribution. When a low molecular weight polymer is administered to the human body, excessive drug release may occur at the early stage. In addition, any residual monomer may be decomposed to reduce pH so that the polymer is decomposed rapidly, which leads to a failure in continued drug release.
Under these circumstances, there has been suggested a method for purifying an amphiphilic block copolymer containing a polylactide derivative as a hydrophobic block by a solvent/non-solvent process. In the method, a methylene chloride/ether system is used as the solvent/non-solvent system to remove monomers, d,l-lactide. Although the method is effective for removing d,l-lactide, stannous octoate used as a catalyst for the polymerization co-precipitates with the block copolymer in the non-solvent, and thus is hardly removed from the block copolymer. Additionally, due to very low boiling points of ethers used as the non-solvent, the method is not suitable for commercialization. The catalyst, stannous octoate, still remaining after the solvent/non-solvent purification, may accelerate hydrolysis of polylactide derivatives, resulting in a decrease in the molecular weight of the block copolymer, and thus a decrease in pH.
As another approach, there has been suggested a method for removing monomers without using any solvent. In the method, after an amphiphilic copolymer containing a polylactide derivative is prepared, unreacted lactide monomers are removed under a high-temperature vacuum condition via sublimation based on the sublimation property of lactide. The method is favorable to commercialization. However, the method has difficulty in reducing the content of residual monomers to 1 wt % or less. In addition, such long-period high-temperature vacuum conditions interrupt control of a desired molecular weight due to the pyrolysis of the resultant polymer. Further, an organometal catalyst used for the polymerization still remains after carrying out the method.
Meanwhile, US Patent Publication No. 2005/0238618 discloses a method for purifying low molecular weight d,l-polylactic acid via liquid/liquid phase separation. A phase separation phenomenon occurs when the polymer obtained after polymerization is heated and dissolved in methanol or ethanol, and then refrigerated and stored at −78° C. Low-molecular weight polylactic acid is dissolved in the upper organic solvent layer, while high-molecular weight polylactic acid is solidified in the lower layer. The lower layer is separated and the solvent of the lower layer is removed via distillation to remove monomers and oligomers. It is described that the method provides highly pure d,l-polylactic acid having a narrow molecular weight distribution. However, since the low-temperature refrigeration causes a drop in the solubility of unreacted lactide monomers and precipitation of the unreacted monomers, it is difficult to remove the unreacted monomers. Moreover, amphiphilic block copolymers are not liquid/liquid phase separable even under low-temperature refrigeration. Therefore, the method is not suitable for the purification of amphiphilic block copolymers.